CHronic Nonbacterial Osteomyelitis International Registry (CHOIR)

CHronic Nonbacterial Osteomyelitis International Registry (CHOIR)

The objective of the study is to establish a prospective disease registry for chronic recurrent multifocal osteomyelitis (CRMO)/chronic nonbacterial osteomyelitis (CNO) in order to investigate the natural history of the disease and the responses of patients to different clinical managements over 10 years.

Study Overview

• Status: Recruiting
• Conditions: Chronic Recurrent Multifocal Osteomyelitis; Chronic Nonbacterial Osteomyelitis
• Intervention / Treatment: Drug: Methotrexate; Drug: Sulfasalazine; Drug: Leflunomide; Drug: Etanercept; Drug: Adalimumab; Drug: Certolizumab; Drug: Infliximab; Drug: Golimumab; Drug: Pamidronate; Drug: Zoledronic acid; Drug: NSAID

Detailed Description

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease that mainly affects children and adolescents. Clinical presentations range from mild and sometimes limited unifocal disease to severe, chronically active or recurrent inflammation of multiple bones. The latter is referred to as chronic recurrent multifocal osteomyelitis (CRMO). Here we will use the term "CNO" to refer to the entire spectrum of this disease. CNO can be complicated by vertebral compression fractures, kyphosis, and leg length discrepancy when it is not recognized early or treated adequately. The diagnosis of CNO is made by excluding alternatives in the differential diagnosis including malignancy (leukemia, lymphoma, and primary or metastatic bone tumors), Langerhans cell histiocytosis, and infection. Clinical assessment in conjunction with serum inflammatory parameters and imaging studies, particularly magnetic resonance imaging (MRI), are crucial for the diagnosis and monitoring of disease activity of CNO1.

Because of significant variation in clinical treatment practices among pediatric rheumatologists, standardized treatment regimens (consensus treatment plans, CTPs) have been developed within the Childhood Arthritis and Rheumatology Research Alliance (CARRA), a North American organization comprised of pediatric rheumatologists and researchers, for CNO patients with an NSAID-refractory course and/or with active spinal lesions2. These CTPs provide an opportunity for pediatric rheumatologists to conduct comparative effectiveness research on CNO through prospective data collection. CRMO/CNO workgroup is comprised of pediatric rheumatologists from North America as well as international colleagues who are interested in collaborating in CNO research. Furthermore, risk factors of severe disease have been described by Wipff et al. based on a large retrospective cohort study3. Their results may be validated by an independent prospective cohort study. To date, there has been only one prospective study on CNO since its first description in 19724. Therefore, we propose to establish this international registry of patients with CNO to accomplish above goals. Long-term outcomes of CNO remains unknown due to the lack of prospective study. It has been estimated that at least 50% of CNO patients continue to need medications for CNO during adulthood. Our study will collect the clinical data and provide valuable data to characterize the long-term outcomes.

• Study Type: Observational
• Enrollment (Estimated): 2000

Contacts and Locations

• Study Contact: Name: Yongdong (Dan) Zhao, MD, PhD; Phone Number: 206-987-2000; Email: crmoresearch@seattlechildrens.org

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98105
      • Recruiting
      • Seattle Children's Hospital
      • Contact: Joshua Scheck, BS; Phone Number: 206-987-2000; Email: crmoresearch@seattlechildrens.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 17 years (Child, Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Children with a diagnosis of CNO/CRMO who have failed NSAIDs and/or with active spinal lesion

Description

Inclusion Criteria:

• - Age at enrollment is equal to or younger than 21 years of age
• Presence of bone edema on STIR or T2 fat saturation sequence on MRI within 12 weeks of enrollment
• Whole body imaging evaluation (either WB MRI or bone scintigraphy)
• Bone biopsy to exclude infection or malignancy unless bone lesions follow typical distribution or there is IBD, psoriasis, or palmar plantar pustulosis

Exclusion Criteria:

• - History of or current malignancy
• Current infectious osteomyelitis
• Contraindication to the selected treatment agent

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
disease modifying anti-rheumatic drug, DMARD; Methotrexate 1 mg/kg (max 25 mg) PO or SQ weekly; Sulfasalazine 30 mg/kg (max 1000 mg) PO twice daily; Leflunomide 10-20 mg PO daily	Drug: Methotrexate; second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs; Drug: Sulfasalazine; second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs; Other Names: Azulfidine; Drug: Leflunomide; second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs; Other Names: areva
tumor necrosis factor inhibitor, TNFi; Adalimumab (subcutaneous) 10-40 mg SQ every other week; Etanercept (subcutaneous) 12.5-50 mg SQ every week; Infliximab (intravenous) 10 mg/kg (max 1000 mg) i.v. at week 0,2, 6 then every 4 weeks; Golimumab (subcutaneous or intravenous) 2 mg/kg (max 200 mg) at every 4 weeks	Drug: Etanercept; second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs; Other Names: enbrel; Drug: Adalimumab; second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs; Other Names: humira; Drug: Certolizumab; second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs; Other Names: cimzia; Drug: Infliximab; second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs; Other Names: remicade, inflectra; Drug: Golimumab; second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs; Other Names: simponi
bisphosphonate; Pamidronate 1 mg/kg (max 90 mg) (intravenous)*:Option 1: every month Option 2: 3 consecutive days every 3 months; Zoledronic acid 0.0125-0.05 mg/kg (max 4mg) (intravenous): every 3-6 months. * Both options may use lower dose of 0.5 mg/kg at the initiation of the treatment. All options allow concurrent use of NSAIDs.	Drug: Pamidronate; second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs; Other Names: Aredia; Drug: Zoledronic acid; second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs
non-steroidal anti-inflammatory drugs; Naproxen 10 mg/kg (max 500 mg) PO twice daily; Indomethacin 1 mg/kg (max daily dose 150 mg) PO twice or three times daily; Meloxicam 0.1-0.3 mg/kg (max 15 mg) PO daily; Piroxicam 10-20 mg PO daily; Ibuprofen 10 mg/kg (max 800 mg) PO 3-4 times daily	Drug: NSAID; first-line treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The change of CNO disease activity score	Disease activity score is calculated as the sum of number of clinical lesion count, patient global assessment (0-10), physician global assessment (0-10)	3-6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total number of CNO lesions on MRI	The total number of CNO lesions from MRI as previously described (Zhao, et al. J Rheum 2019) will be used to monitor response in a subset	3-6 months
Safety monitoring	Serious adverse events including infections that require IV antibiotics, malignancy, hematological, hepatic, dermatological side effects will be reported	5 years

Collaborators and Investigators

• Sponsor: Seattle Children's Hospital
• Collaborators: Hospital for Special Surgery, New York; Mansoura University; Boston Children's Hospital, Boston, MA, USA; Joseph M Sanzari Children's Hospital, Hackensack University Medical Center, Hackensack, NJ, USA; Riley Children's Hospital, Indianapolis, IN, USA; University of North Carolina, Chapel Hill, NC, USA; Royal Children's Hospital, Melbourne, Australia; Hacettepe University, Ankara, Turkey; Bambino Gesù Children's Hospital, Rome, Italy; University of British Columbia, Vancouver, BC, Canada; Meyer Children's Hospital, Florence, Italy; University of Utah, Salt Lake City, UT, USA; University of Iowa Carver College of Medicine, Iowa City, IA, USA; Ann & Robert Lurie Children's Hospital of Chicago, Chicago, IL, USA; Palacky University Olomouc Institute of Molecular and Translational Medicine, Olomouc, Czechia; Alder Hey Children's NHS Foundation Trust Hospital, Liverpool, UK; University of Calgary, Calgary, Alberta, Canada

Publications and helpful links

General Publications

• Zhao Y, Wu EY, Oliver MS, Cooper AM, Basiaga ML, Vora SS, Lee TC, Fox E, Amarilyo G, Stern SM, Dvergsten JA, Haines KA, Rouster-Stevens KA, Onel KB, Cherian J, Hausmann JS, Miettunen P, Cellucci T, Nuruzzaman F, Taneja A, Barron KS, Hollander MC, Lapidus SK, Li SC, Ozen S, Girschick H, Laxer RM, Dedeoglu F, Hedrich CM, Ferguson PJ; Chronic Nonbacterial Osteomyelitis/Chronic Recurrent Multifocal Osteomyelitis Study Group and the Childhood Arthritis and Rheumatology Research Alliance Scleroderma, Vasculitis, Autoinflammatory and Rare Diseases Subcommittee. Consensus Treatment Plans for Chronic Nonbacterial Osteomyelitis Refractory to Nonsteroidal Antiinflammatory Drugs and/or With Active Spinal Lesions. Arthritis Care Res (Hoboken). 2018 Aug;70(8):1228-1237. doi: 10.1002/acr.23462. Epub 2018 Jul 12.
• Zhao Y, Ferguson PJ. Chronic Nonbacterial Osteomyelitis and Chronic Recurrent Multifocal Osteomyelitis in Children. Pediatr Clin North Am. 2018 Aug;65(4):783-800. doi: 10.1016/j.pcl.2018.04.003.
• Oliver M, Lee TC, Halpern-Felsher B, Murray E, Schwartz R, Zhao Y; CARRA SVARD CRMO/CNO workgroup. Disease burden and social impact of pediatric chronic nonbacterial osteomyelitis from the patient and family perspective. Pediatr Rheumatol Online J. 2018 Dec 14;16(1):78. doi: 10.1186/s12969-018-0294-1.
• Beck C, Morbach H, Beer M, Stenzel M, Tappe D, Gattenlohner S, Hofmann U, Raab P, Girschick HJ. Chronic nonbacterial osteomyelitis in childhood: prospective follow-up during the first year of anti-inflammatory treatment. Arthritis Res Ther. 2010;12(2):R74. doi: 10.1186/ar2992.
• Voit AM, Arnoldi AP, Douis H, Bleisteiner F, Jansson MK, Reiser MF, Weckbach S, Jansson AF. Whole-body Magnetic Resonance Imaging in Chronic Recurrent Multifocal Osteomyelitis: Clinical Longterm Assessment May Underestimate Activity. J Rheumatol. 2015 Aug;42(8):1455-62. doi: 10.3899/jrheum.141026. Epub 2015 May 15.
• Girschick H, Finetti M, Orlando F, Schalm S, Insalaco A, Ganser G, Nielsen S, Herlin T, Kone-Paut I, Martino S, Cattalini M, Anton J, Mohammed Al-Mayouf S, Hofer M, Quartier P, Boros C, Kuemmerle-Deschner J, Pires Marafon D, Alessio M, Schwarz T, Ruperto N, Martini A, Jansson A, Gattorno M; Paediatric Rheumatology International Trials Organisation (PRINTO) and the Eurofever registry. The multifaceted presentation of chronic recurrent multifocal osteomyelitis: a series of 486 cases from the Eurofever international registry. Rheumatology (Oxford). 2018 Jul 1;57(7):1203-1211. doi: 10.1093/rheumatology/key058. Erratum In: Rheumatology (Oxford). 2018 Aug 1;57(8):1504. doi: 10.1093/rheumatology/key143.
• Wu EY, Oliver M, Scheck J, Lapidus S, Akca UK, Yasin S, Stern SM, Insalaco A, Pardeo M, Simonini G, Marrani E, Wang X, Huang B, Kovalick LK, Rosenwasser N, Casselman G, Liau A, Shao Y, Yang C, Mosa DM, Tucker L, Girschick H, Laxer RM, Akikusa JD, Hedrich CM, Onel K, Dedeoglu F, Twilt M, Ferguson PJ, Ozen S, Zhao Y. Feasibility of Conducting Comparative Effectiveness Research and Validation of a Clinical Disease Activity Score for Chronic Nonbacterial Osteomyelitis. J Rheumatol. 2023 Oct;50(10):1333-1340. doi: 10.3899/jrheum.2022-1323. Epub 2023 Jul 1.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2018
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): August 1, 2050

Study Registration Dates

• First Submitted: January 18, 2021
• First Submitted That Met QC Criteria: January 22, 2021
• First Posted (Actual): January 26, 2021

Study Record Updates

• Last Update Posted (Actual): July 30, 2024
• Last Update Submitted That Met QC Criteria: July 27, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Infectious; Osteomyelitis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Dermatologic Agents; Bone Density Conservation Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Tumor Necrosis Factor Inhibitors; Etanercept; Adalimumab; Methotrexate; Infliximab; Leflunomide; Golimumab; Zoledronic Acid; Certolizumab Pegol; Sulfasalazine; Pamidronate
• Other Study ID Numbers: 1232

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No